Alkylphospholipids represent a new class of lipid-related compounds that exhibit anticancer activity. Alkylphospholipids exhibit very unique patterns of in vitro cell growth inhibition that are distinctly different from those of most cytotoxic agents, by accumulating in cell membranes and modifying cell signaling pathways [Arthur and Bittman, Biochim Biophys Acta 1998, 1390:85-102].
Miltefosine is an alkylphospholipid licensed in Europe as a topical application for treatment of cutaneous metastases from breast cancer. It is also used in an oral formulation to treat leishmaniasis. Miltefosine exhibits gastrointestinal toxicity.
Perifosine (1,1-dimethyl-4-[[(octadecyloxy)hydroxyphosphinyl]oxy]-piperidinium inner salt) is a synthetic alkylphospholipid identified as a more active and better tolerated alternative to miltefosine [Hilgard et al. Eur J Cancer 1997, 33:442-446]. Perifosine exhibited marked activity in animal and human tumor cell lines resistant to standard chemotherapeutic agents, with relative sparing of normal cells. Oral administration of perifosine was shown to be effective against tumors in several in vivo animal models.
Perifosine has been shown to inhibit or otherwise modify signaling through a number of different signal transduction pathways, including, for example, Akt, p21 and JNK.
Akt activation has been shown to be important in a number of different cancer types, particularly cancers characterized by a poor prognosis. Perifosine blocks phosphorylation of Akt, thereby inhibiting activation of Akt [Kondapaka et al., Mol Cancer Ther 2003, 2:1093-1103; Ruiter et al., Anticancer Drugs 2003, 14:167-173].
Perifosine also stimulates the SAPK/JNK cascade, which normally promotes apoptosis following unusual stress. Perifosine may increase levels of apoptosis induced by radiotherapy [Verheij et al., American Society of Clinical Oncology 2004, New Orleans La.].
Capecitabine, which is marketed as Xeloda®, is an orally administered fluoropyrimidine that is converted to 5-fluorouracil in tumors. Capecitabine is indicated for the following treatments:
first-line treatment of metastatic colorectal carcinoma;
adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor;
treatment of metastatic breast cancer in combination with docetaxel, after failure of anthracycline-containing chemotherapy; and
monotherapy for metastatic breast cancer resistant to paclitaxel, when an anthracycline-containing regimen is not indicated.
The Xeloda® Prescribing Information [1999: Roche Inc.], which is incorporated herein by reference in its entirety, lists recommendations for capecitabine administration and relevant data.
The recommended dose of capecitabine for all of the above-mentioned indications is 1250 mg/m2, administered orally twice daily (i.e., 2500 mg/m2 total daily dose) in 3-week cycles consisting of administration for 2 weeks followed by a 1-week rest period. Upon appearance of Grade 2, 3 or 4 toxicity, it is recommended to interrupt capecitabine treatment to resolve the toxicity to Grade 0 or 1, after which capecitabine treatment may be resumed. Resumption of capecitabine treatment following Grade 3 toxicity is recommended to be at 75% of the original dose. Resumption of capecitabine treatment following Grade 4 toxicity, if performed, is recommended to be at 50% of the original dose.
Adverse events or side effects caused in patients receiving capecitabine are similar to those in patients receiving 5-fluorouracil, and include gastrointestinal disorders (e.g., diarrhea, nausea, stomatitis, vomiting, abdominal pain), hand-foot syndrome, EKG changes, myocardial infarction, angina, neutropenia, anemia, thrombocytopenia and hyperbilirubinemia.
Capecitabine is contraindicated in patients with hypersensitivity to 5-fluorouracil, in patients with dihydropyrimidine dehydrogenase deficiency and in patients with severe renal impairment. Dose reduction is recommended for patients with moderate renal impairment. It is recommended to avoid pregnancy and nursing when receiving capecitabine. Anticoagulant doses may need to be modified when receiving capecitabine.
Peak capecitabine blood level occurs about 1.5 hours after administration, with peak 5-fluorouracil level occurring slightly later (2 hours). Food reduces both the rate and extent of capecitabine absorption. The elimination half-life of both capecitabine and 5-fluorouracil is about ¾ of an hour.
Colorectal cancer is one of the leading causes of cancer-related death in the Western world. Treatment of colorectal cancer often utilizes 5-fluorouracil as a chemotherapeutic agent. The FOLFIRI and FOLFOX regimens combine 5-fluorouracil with leucovorin and either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). Tumor resistance to 5-fluorouracil may be mediated by upregulation of NF-κB [Voboril et al., J Surg Res 2004, 120:178-188]. Bevacizumab, cetuximab and panitumumab are also used either in combination with chemotherapy or as a single agent for treating colorectal cancer.
Nearly 40% of colorectal tumors have alterations in the PI3/Akt pathway, including activating mutations in p110α (a PI3-kinase subunit) or loss of PTEN (a tumor suppressor protein which regulates the PIS/Akt pathway) [Brugge et al., Cancer Cell 2007, 12:104-107; Rychahou et al., PNAS 2008, 105:20315-20320; Sawai et al., BMC Gastroenterol 2008, 8:56].
U.S. Patent Application No. 2004/0097470 describes a use of alkylphosphocholines in combination with antitumor medicaments for the treatment of oncoses.
International Patent Application PCT/DE99/03952 (published as WO 00/033917) describes a combination of an antineoplastic alkylphospholipid with an antiestrogen such as tamoxifen.
International Patent Application PCT/US2006/002988 (published as WO 06/081452) describes methods of treating cancer by co-administration of perifosine and a second chemotherapeutic agent, such as paclitaxel, docetaxel, gemcitabine and trastuzumab.
Additional background art includes Hilgard et al., Advances in Experimental Medicine and Biology 1996, 416:157-164; Hilgard et al., Cancer Chemotherapy and Pharmacology 1993, 32:90-95; Spruss et al., J. Cancer Research and Clinical Oncology 1993, 119:142-149; Berkovic et al., Leukemia 1997, 11:2079-2086; and Georgieva et al., Cancer Letters 2002, 182:163-174.